The genetic mutation in cystic fibrosis (CF) affects the expression of a regulator of cellular ion transport. The primary manifestations of this defect occur in the lung, liver, and pancreas. Phase-I clinical trials of CF-gene replacement, using adenoviral (AdV) vectors which are known to efficiently deliver genes to the lung and liver, have had limited success because host responses to the AdV reduce the duration of transgenic expression of CFTR. CD4+ lymphocytes are critical to these responses and depleting anti-CD4 antibody prolongs AdV expression in the lungs of rodents. We plan to test various immunosuppressive protocols in rhesus monkeys to evaluate their effect on transgene expression of AdV vectors inoculated into the lung. For this pilot project, a rhesus monkey was inoculated intrabronchially with an AdV vector containing the LacZ reporter gene. The inoculation site was biopsied 3 days later, and transgene expression was demonstrated. These preliminary results were used in a grant application, which has been partially funded by the Cystic Fibrosis Foundation. Additional studies are currently being planned.